Magnesium-containing products and uses thereof

ABSTRACT

A composition including a hydrate form of magnesium oxide, denoted as MgO.(H2O)n, at a concentration ranging from 1 to 100 weight percent (wt %), where n is any value from 0.1 to 2. The composition may further include MgO at a concentration ranging from 0 to 99 wt %; or Mg(OH)2, at a concentration ranging from 0 to 99 wt %; or Mg(OH)2 at a concentration ranging from 0 to 99 wt %, and MgO, at a concentration ranging from 0 to 99 wt %.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/807,660 filed on Nov. 9, 2017, which is a continuation of U.S. patentapplication Ser. No. 15/180,142 filed on Jun. 13, 2016, now U.S. Pat.No. 9,849,148 which is a division of U.S. patent application Ser. No.14/194,833 filed on Mar. 3, 2014, which claims the benefit of priorityof U.S. Provisional Patent Application No. 61/826,736 filed on May 23,2013.

The contents of the above applications are all incorporated by referenceas if fully set forth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to the field of supplemental products, andmore particularly, but not exclusively, to novel magnesium(Mg)-containing products, method of preparing same and uses thereof asmagnesium supplements with enhanced bioavailability in humans.

Magnesium is a natural element widely diffused in living organisms,especially in mammals, wherein the largest concentration thereof occursin bones. The participation of magnesium ions in the human body has beenestablished in most reactions of carbohydrates, lipids, nucleic acids,and in protein metabolism.

Magnesium is the fourth most abundant cation in the human body and playsan essential physiological role in many of its functions. This role isachieved through two important properties of magnesium; the ability toform chelates with important intracellular anionic-ligands, especiallyATP, and its ability to compete with calcium for binding sites onproteins and membranes. By competing with calcium for membrane bindingsites and by stimulating calcium sequestration by sarcoplasmicreticulum, magnesium helps to maintain a low resting intracellular freecalcium ion concentration which is important in many cellular functions.The electrical properties of membranes and their permeabilitycharacteristics are also affected by magnesium.

Magnesium, being a normal component of the blood plasma and a calciumantagonist, takes part in the muscle contraction mechanism and is vitalfor the action of a number of enzymes. Magnesium balance in organism istightly controlled by the dynamic action of intestinal absorption,exchange with bone, and renal excretion.

Magnesium is estimated to be distributed in the body as follows: 53% inthe bone, 27% in muscle, 19% in soft tissue, 0.5% in erythrocytes, and0.3% in serum. Of the serum magnesium, 33% is protein-bound, 12% iscomplexed to anions, and 55% is in the free ionized form. Totalmagnesium stores in the body average 24 grams (2000 mEq) elementalmagnesium, and a normal serum concentration is in the range of 1.7-2.5mg/dL (1.4-2.1 mEq/L).

Mg is transported to the different body compartments in the bloodplasma, either as free ionized Mg, bound to relatively small(ultrafiltrable) complexes (e.g. citrate) or bound to proteins (albumin,globulin), which are not ultrafiltrable. The concentration of Mg inserum is kept relatively constant. However, it has been shown that thereis no apparent correlation between serum and tissue magnesium levels,with exception of bone and interstitial fluid, and therefore serummagnesium measurements do not accurately reflect the amount of magnesiumpresent in the body.

Magnesium excretion is the main pathway for regulating Mg levels in theblood. About 70-80% of plasma Mg (ultrafiltrable Mg) is filtered in thekidney. Of this ultrafiltrable Magnesium, 20-25% is reabsorbed by theproximal tube, 50-60% in the loop of Henle, and 5% in terminal segments,while the remainder (5-20%) is excreted in the urine. Magnesium isexcreted from the gastrointestinal tract at a rate of approximately 2mEq/day. Further significant loss of magnesium can be caused by drugssuch as amphotericin B, cisplatin, digoxin, pentamidine, gentamicin, andloop diuretics via renal wasting of magnesium in the renal tubule.

The daily magnesium requirement for humans ranges from 5 to 10 mg/per kgbody weight, and is normally supplied through the food, particularlyvegetables. However, as the magnesium food content in the Western worldis consistently reducing, magnesium deficiency, or hypomagnesaemia, hasbecome a prevalent condition. While the average daily intake ofmagnesium at the beginning of the 20th century was 410 mg, today it isonly 200-300 mg. This is attributed to the processed nature of thecontemporary diet (Seelig and Rosanoff, 2003).

The current daily Recommended Dietary Allowances for magnesium is 420mg/day for males and 320 mg/day for females above 31 years, with anadditional 300 mg/day during pregnancy or physical growth. Surveys showthat a substantial number of adults in the United States fail to consumerecommended daily amounts of magnesium. Dietary surveys show that theaverage intake in many western countries is less than the RDA (Saris etal., 2000). In a population-based study of 30-year old Israelis, about60% had magnesium deficiency (Shechter, 2010; Seelig, 1964; Centers forDisease Control and Prevention, 1994).

Magnesium homeostasis is essential for many intracellular processes anddepends on the balance of intestinal absorption and renal excretion.Hypomagnesaemia may arise from various disorders. A magnesiumdeficiency, or hypomagnesaemia, is common in hospitalized patients,especially in the elderly with coronary artery disease (CAD) and/orthose with chronic heart failure. Hypomagnesemia is often associatedwith increased incidence of diabetes mellitus, metabolic syndrome,mortality rate from coronary artery disease (CAD) and all cause.

Hypomagnesaemia is also associated to abnormal muscle excitability aswell as convulsions, to psychiatric disturbances, and to calcium and/orpotassium abnormalities.

Diminished content of magnesium in blood serum contributes to thedevelopment of hypercalcemia, spasm of arterioles, and the occurrence ofmuscular convulsions and trophic disorders and thus plays an essentialrole in the pathogenesis of changes of the blood flow and trophicdisorders.

Magnesium deficiency can occur in babies from birth, when the mother wasalready depleted of her own magnesium reserves, or when the baby ispoorly supplied with magnesium, and/or undergoes high magnesium lossesfrom his or her organism. When encountered in an adolescent, adult oraged person, a magnesium deficiency can be also ascribed to generallystressing conditions, chronic intoxication or disease, to malabsorption,to alcohol or drugs abuse, as well as to hormone pathologies that causemagnesium losses for long time periods. A magnesium deficiency referableto a poor supply can be also due to, e.g., growth, pregnancy, breastfeeding, anorexia, vomiting, overload of calcium, of vitamin D, ofphosphorus, of alkalizing products, or excessive intake of alimentaryfiber, low calorie diets, alcoholism, etc. A magnesium deficiencyreferable to defects in magnesium metabolism can be due to, e.g., stressor neurosis, nervous disorders or endocrine-metabolic disorders.

In addition to conditions or disorders caused by magnesium deficiency,magnesium supplements have been shown to have a therapeutic effect inmany other conditions or disorders, including, for example,constipation, preeclampsia, leg cramps, cerebral palsy, depression,asthma, cardiovascular diseases, ischemic heart disease, cardiacarrhythmias, hypertension, pregnancy-induced hypertension, strokes,cerebrovascular diseases, osteoporosis, alcohol withdrawal, pretermlabor, fatigue, renal stones, kidney, stones, headache, migraine,altitude sickness, premenstrual syndrome, fibromyalgia, muscle weakness,insulin resistance, bronchospasms, hyperlipidemia, mitral valveprolapse, neonatal encephalopathy, and diabetes mellitus.

Magnesium supplementation has been shown to improve myocardialmetabolism, to inhibit calcium accumulation and myocardial cell death;to improve vascular tone, peripheral vascular resistance, and afterloadand cardiac output, to reduce cardiac arrhythmias and to improve lipidmetabolism.

A magnesium deficiency or excess in an organism cannot be quantified asan absolute value, as the magnesium level in the blood is not relatedwith the presence thereof in the deposit sites, as discussedhereinabove. Generally speaking, the means for detecting the magnesiumbody contents include the detection of blood levels of magnesium, in thepatient's plasma or in the serum (whose anomalies generally indicate adisorder in magnesium metabolism and are, normally, the starting pointfor a set of further specific tests); the detection of magnesium levelsin the urine (which gives a measure of the elimination of magnesium viaurine, and is normally associated with protein intake, being the Mg/urearatio in the urine quite constant); the detection of magnesium levels inthe spinal fluid; the detection of erythrocytic magnesium (which showsthe amount of Mg contained in the bone marrow when erythropoiesis occursand allows, therefore, an indirect medullary exploration as concernsmagnesium); the detection of lymphocytic magnesium; nuclear magneticresonance with ²⁵Mg (which evidences any modifications in thesubcellular distribution of magnesium and in the differentchemical-physical structures); and, the detection of magnesium contentsin the patient's bones, muscles or any other tissue or organ ofinterest.

In view of the widespread recognition of the involvement of magnesium ina variety of disorders and conditions, and the increased need inmagnesium supplementation, magnesium-containing products became a highlyrecommended standard of care.

Herein throughout, in the context of magnesium-containing products,magnesium supplements, magnesium formulations and/or magnesium therapy,the term “magnesium” refers to Mg⁺² ions, either in a form of free ionsin a salt or in a form of a complex.

Currently available Mg-containing products that are aimed at magnesiumsupplementation are formulated mainly for intravenous or oraladministration. An oral route of administration is more convenient, andusually the safest and least expensive, whereas intravenousadministration must be performed by a health care worker, and hasadditionally sparked some concern as to possible elevation of serumlevels of magnesium to the toxic range. However, the decreasedabsorption associated with oral administration poses a significantobstacle in administration (The Merck Manual Home Health Handbook, 2009,Chapter 10).

When administered orally, magnesium was shown to be absorbed primarilyin the small intestine in the ileum and jejunum, and the degree ofabsorption has been shown to depend upon the amount of magnesium alreadypresent in the diet and the amount of magnesium administered. Asindicated by radioactive ²⁸Mg studies, absorption begins approximately 1hour after oral intake, plateaus after 2-5 hours, and then declines.After 6 hours Mg absorption is about 80% complete.

Studies have shown that inorganic magnesium salts may have abioavailability equivalent to organic magnesium salts, depending on thepreparation (Firoz and Graber, 2001). It has further been shown thatmagnesium salts are converted to magnesium chloride in the stomach(Seelig, 1989). Non-absorbed magnesium (not uptaken by cells), due tohigh oral loads or inefficient absorption, can cause a number of sideeffects, including diarrhea, heartburn, nausea, and upset stomach.

Currently available magnesium-containing products for oraladministration include, for example, magnesium oxide, magnesiumcarbonate, magnesium hydroxide, magnesium citrate, magnesium lactate,magnesium gluconate, magnesium chloride, magnesium aspartate, magnesiumcaprilate, magnesium pidulate and magnesium sulfate. Intravenouslyadministered magnesium includes, for example, magnesium sulfate. It isto be noted that oral administration of acidic magnesium salts, whichgenerate relatively strong acids in the stomach (e.g., magnesiumchloride and magnesium sulfate) is limited by the tolerable amount thatcan be taken, since it can cause non-tolerable acidity in the stomach.

In order for Mg-containing product to be therapeutically effective, itshould be able to release a form of ionized magnesium which can beuptaken into the cells to perform its essential functions. As notedhereinabove, the level of serum magnesium does not necessarily correlateto levels of cellular magnesium, and therefore the identification of aneffective Mg supplementation should be determined by its cellularuptake. Since magnesium has no specific target tissue, itsbioavailability cannot be assessed directly. Therefore, other parameterssuch as retention, absorption, and urinary excretion are used as ameasure for magnesium oral bioavailability. Intravenously administeredmagnesium is considered to be 100% bioavailable.

Several independent studies have been performed in order to evaluate theabsorption of different forms of orally administered magnesiumsupplements. However, conflicting data regarding the absorption rates ofmagnesium as a function of the supplement formulation are found in theart.

Magnesium oxide capsules were better absorbed than magnesium-L-aspartateHCL tablets as measured by urinary excretion of magnesium, while plasmamagnesium levels remained unchanged (Muhlbauer et al., 1991). Magnesiumoxide preparation improved serum magnesium in those with low basal serumlevels, but not in those with normal/high serum levels, in a study ofmagnesium absorption in subjects given magnesium-enriched diets followedby either magnesium oxide or magnesium phosphate plus oxide (Altura etal., 1994). The superiority of magnesium oxide absorption over magnesiumglycerophosphate was observed in patients with shortened smallbowel-induced malabsorption (Ross et al., 2001). Another study showedthat MgO was significantly less well absorbed than a comparable amountof Mg citrate as measured by urinary excretion four hours post load(Lindberg et al., 1990). In another study, MgO showed increased urinaryexcretion as compared with a comparable amount of MgCl₂, Mg lactate, andMg aspartate (Firoz and Graber, 2001). However, in other studies(Schuette et al., 1993 and Schuette et al., 1994) there was nosignificant difference observed between uptakes of MgO as compared withMg diglycinate.

Yet another study compared the delivery of MgAc in gelatin capsules tomagnesium chloride in enteric-coated capsules. The lower absorption ofthe enteric-coated capsules was attributed to the 3-5 hour exposurenecessary to fully release the capsule's contents, which reduced thesmall bowel absorptive area to which the Mg is exposed (Fine et al.,1991).

One study on livestock reported that the particle size of the MgOaffects its absorption, a phenomenon which could explain the conflictingresults about MgO absorption (Xin et al., 1989).

Several means have been devised to overcome the poor absorption of MgO.Efforts were made to utilize small MgO particles, yet, are hindered bythe tendency of the magnesium oxide particles to strongly agglomerate.Resulting agglomerates require a high shear force for re-pulverizationat the time of incorporation into absorbable preparations, and thusadversely affect other ingredients in any planned preparations.

The present inventor discovered that a special form of magnesium oxideis useful to overcome not only the problems of agglomeration but alsoprovide enhancing bioavailability of magnesium.

Magnesium oxide, also known as the mineral periclase, can be formed bycalcination at high temperatures from magnesium carbonate (Liu et al,1997), by thermal decomposition of magnesium chloride (Jost et al.1997), or by dehydration of magnesium hydroxide.

The dehydration of magnesium hydroxide (also referred to in the art asbrucite), so as to form magnesium oxide and water has been studiedextensively in the art (Meyer and Yang, 1962; Barnes and Ernst, 1963;Aranovich and Newton, 1996; L'vov et al., 1998).

It has been shown that this reaction occurs under definedpressure-temperature conditions (see, for example, Schramke et al.,1982; and corresponding Background Art FIG. 1, further discussedhereinbelow).

Schramke et al. (1982) used a method of measuring volume changes ofencapsulated samples during the experimentation of the brucite-periclaseequilibrium, in order to avoid quenching problems. The results agreewith data obtained from thermochemical techniques, as reflected inBackground Art FIG. 1. Notably, the curve for the dehydration of bruciteand the curve for the hydration of periclase do not demonstrate the samevalues.

Meyer and Yang (1962) reported that the dehydration curve obtained bytemperature quenching and the hydration curve obtained by pressurequenching are about 40° C. apart at elevated pressures. They proposedthat the difference between the 2 curves is due to the formation of anintermediate phase, corresponding to a distorted periclase which rapidlyrehydrates during quenching.

Barnes and Ernst (1963) investigated the brucite periclase equilibriumat pressures up to 2 kbar using cold-seal hydrothermal pressure vesselswith water as the pressure medium. In their study, they developed twoprocedures to avoid confusing the effects of a back reaction during thequench.

Johnson and Walker (1993) determined accurately the brucite dehydrationequilibrium from 1 to 15 GPa. The approach adopted was a combination ofdifferential thermal analysis (DTA) and quenching experiments. Thequenching experiments are more reliably interpreted than in otherstudies because thermal gradients cause diffusive migration of periclaseand H₂O to different regions of the experimental charge. This separationfacilitates quenching of periclase in experiments outside the brucitestability field. In the quenching experiments, samples were brought tothe desired pressure and temperature, held there for 30 minutes, andthen quenched by shutting off furnace power. Background Art FIG. 2presents an experimentally determined phase diagram for the dehydrationof brucite determined by differential thermal analysis (circles), andquenching techniques (squares), and additionally presenting an interfacein which magnesium hydroxide and magnesium oxide were stable (opensquares), and temperatures at which both brucite and periclase werestable (half-shaded squares)).

Additional experiments and data from Yamaoka et al., 1970; Irving etal., 1977; Kanzaki, 1991; and Leinenweber et al., 1991, have shownsimilar results (see, Johnson and Walker, 1993).

Ball and Taylor (1961) have studied the dehydration process of bruciteto periclase using X-rays measurements and found that this processinvolves a formation of spinel-like intermediate, which gave “extra”reflections, and was obtained when a pure brucite crystal was heated inair to 800° C. for 45 minutes. Ball and Taylor have suggested thatduring the formation of periclase, donor and acceptor regions aredeveloped in the brucite crystal, and that the reaction proceeds not byloss of hydroxyl ions, but rather by gain of cations and loss ofprotons. The formed cations migrate into the donor regions, and theirhydroxyl ions provide all the oxygen for the water that is formed, asshown in Background Art FIG. 3. Ball and Taylor have assumed that theformed spinel-like intermediate has a molecular formula of Mg₃O₄H₂,which corresponds to a molecule of water to which 3 molecules of MgO arecomplexed to form a kind of hydrate.

Ahdjoudj and Minot (1998) describe ab initio periodic Hartree-Fockcalculations of water molecules on MgO and teach that the water moleculedoes not dissociate on MgO and is adsorbed parallel to the surface, withthe main interaction concerning the Mg from the surface and thep-orbital electron pair of the water.

Means for providing magnesium to the human body as a supplement havebeen proposed in the art. Despite the ability of existing magnesiumsupplements to increase magnesium levels to some extent, there is aconsiderable need for an improved magnesium-containing composition, ableto enhance the uptake of magnesium in humans. The present inventionsatisfies these needs due to enhanced bioavailability of a specifichydrate form of magnesium oxide, and provides manifestative healthbenefits as well.

SUMMARY OF THE INVENTION

The present invention, in some embodiments thereof, relates to the fieldof supplemental products, and more particularly, but not exclusively, tonovel magnesium (Mg)-containing products, processes of preparing sameand uses thereof as magnesium supplements to provide enhancedbioavailability of magnesium in humans. In particular, the presentinvention relates to a composition including a hydrate form of magnesiumoxide, denoted as MgO.(H₂O)n, at a concentration ranging from 1 to 100weight percent (wt %), where n is any value from 0.1 to 2. The inventordiscovered that a special form of magnesium oxide is useful to overcomenot only the problems of agglomeration but also to provide enhancedbioavailability of magnesium.

According to preferred embodiments of the present invention, there isprovided a pharmaceutical composition and a method for preventingmagnesium deficiency in the humans and non-humans, the method comprisingorally administering a therapeutically effective amount of thepharmaceutical composition which comprises an effective amount of aspecial hydrate form of magnesium oxide, which is denoted herein asmagnesium oxide hydrate MgO.(H₂O)n, extracted from the Dead Sea(Israel).

The present invention also relates to the use of a magnesium oxidehydrate of the form MgO.(H₂O)n, where n=0.1 to 2, in the manufacture ofa magnesium supplement.

According to some embodiments of the invention, the magnesium oxide-typecomposition is selected from the group consisting of MgO, Mg(OH)₂ andMgO.(H₂O)n, wherein n is any value from 0.1 to 2.

According to other embodiments of the invention, the therapeuticallyeffective amount is equivalent to an amount of elemental magnesium thatranges from 50 mg/day to 2000 mg/day.

According to some embodiments of the invention, the pharmaceuticalcomposition is a unit dosage form composition for oral administering andis formulated as a sachets, pills, caplets, capsules, tablets, chewinggums and any other chewable composition, dragee-cores or discrete (e.g.,separately packaged) units of powder, granules, or suspensions orsolutions in water or non-aqueous media.

Further provided in the present invention, there is a pharmaceuticalcomposition characterized as capable of generating free magnesium ionsfrom at least 50% of its magnesium content under physiologicalconditions of a human stomach during a time period that is equivalent toa retention time of the composition in a human stomach.

In other embodiments, the invention provides a magnesium oxide-typecomposition and a method of administering of magnesium supplementationto a subject is described herein. Such a method may comprise oraladministering to the subject at least one unit dosage providingefficient amount of a magnesium oxide-type composition sufficient toenhance bioavailability of magnesium [Mg²⁺]i.

In some embodiments, the present invention provides a method ofdetermining a concentration of magnesium to produce a physiologicaleffect. In some embodiments, the concentration of magnesium is measuredafter fasting in biological fluids selected from blood, serum andplasma. In related embodiments, concentration of intracellular magnesium[Mg²⁺]i is measured with in sublingual epithelial cells through X-raydispersion.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced. The drawingsare illustrative and are not necessarily drawn to scale.

In the drawings:

FIG. 1 (Background Art, taken from Schramke et al. (1982; supra))presents an experimentally determined phase diagram for the dehydrationof brucite, wherein filled figures represent the transition from bruciteto periclase, and empty figures represent the transition from periclaseto brucite, and wherein circles represent data determined by Schramke etal. (1982; supra, denoted “this study”), triangles represent datadetermined by Barnes and Ernst (1963; supra) and squares represent datadetermined by Irving et al. (1977; supra). The shaded area representsthe extrapolation from the end-points of the 8.1 kbar bracket of thisstudy. The solid line is the extrapolated equilibrium curve from thestarting-point at 8.0 kbar and 800° C.

FIG. 2 (Background Art taken from Johnson and Walker, 1993 (supra))presents an experimentally determined phase diagram for the dehydrationof brucite wherein circles represent data determined by differentialthermal analysis, squares represent data determined using quenchingtechniques, open squares indicate an interface in which magnesiumhydroxide and magnesium oxide were stable, half-stippled squaresrepresent temperatures at which both brucite and periclase were stable,and the plus signs are a theoretical phase boundary calculated usingmolecular dynamics.

FIG. 3 (Background Art taken from Ball and Taylor (1961; supra))presents a schematic representation of the acceptor and donor regions,showing the migration of ions in opposite directions and the expulsionof water from the donor region, during the transformation of brucite topericlase.

FIG. 4 presents an optical image of a crystal of a magnesium-containingcomposition according to some embodiments of the present invention.

FIGS. 5A-5C present images of a dissolution assay testing dissolution ofvarious magnesium-containing samples. FIG. 5A shows the experimentalsetup, with a MgO/MgO.(H₂O)n-containing sample at the center flask.FIGS. 5B and 5C show the magnesium citrate-containing samples.

DETAILED DESCRIPTION OF THE INVENTION

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of variousalternatives to the embodiments or of being practiced or carried out invarious ways.

In a search for an effective magnesium source that can be efficientlyused orally as a magnesium-containing supplement, it was uncovered thatmagnesium oxide salts, e.g., from the Dead Sea (Israel), exhibitimproved pharmacological effects, particularly in terms of cellularuptake (intracellular absorption) and, thus, exhibit a superiorperformance, as compared to other currently available Mg-containingsupplements.

More particularly, it was uncovered that products containing uniquemagnesium oxide salts from the Dead Sea exhibit enhanced dissolution andconsequently enhanced generation of Mg²⁺ ions, under acidic conditions.In parallel, it was discovered that oral administration of productscontaining these specific magnesium oxide salts results in elevatedlevels of intracellular magnesium [Mg²⁺]i, which were not observed whenother magnesium-containing products were used.

Herein throughout, the expression “Mg-containing product” encompassesany composition, formulation, unit dosage form, and the like, whichcomprises a magnesium form that is capable of releasing Mg⁺² ions.

In the broadest scope of the invention, the magnesium-containingproducts disclosed herein comprise a hydrate form of magnesium oxide,preferably from the Dead Sea. Without being bound to theory, t washypothesized by the inventor, with reference to magnesium salts from theDead Sea, that the extreme climatic conditions of this region have animpact on the formation of such a unique and specific form of Magnesiumoxide which exhibits X-ray powder patterns characteristic of a hydrateform of MgO (see, Ball and Taylor, 1961, supra). This hydrate form ofmagnesium oxide is a fine, slightly gray powder. According to preferredembodiments, this magnesium oxide hydrate is taken, as is, from the DeadSea and used in an unprocessed form. While such a hydrate compound canbe manufactured in synthetic form for use in the pharmaceuticalcompositions of the present invention, it is much more costly to preparein this fashion.

According to the studies discussed in the Background section hereinaboveand summarized in FIGS. 1 and 2, a hydrate form of magnesium oxide couldbe obtained by those skilled in the art. The FIGS. 1 and 2 demonstratethat the brucite <->periclase transition involves three possible phases:magnesium oxide (MgO; periclase), water, and magnesium hydroxide(Mg(OH)₂; brucite). The curve expresses the conditions at which themagnesium hydroxide releases the water (H₂O) molecule, and thusrepresents the point where a hydrate form of magnesium oxide monohydratemay be formed (prior to the formation of separate phases of MgO andwater).

Thus, according to an aspect of some embodiments of the presentinvention there is provided a composition which comprises:

MgO, at a concentration ranging from 0 to 99 weight percent (wt %);

Mg(OH)₂, at a concentration ranging from 0 to 99 wt %; and

MgO.(H₂O)n, at a concentration ranging from 1 to 100 wt %, wherein n isany value from 0.1 to 2.

The disclosed composition thus comprises a hydrate form of magnesiumoxide, which is denoted herein as MgO.(H₂O)n. The phrases “hydrate formof magnesium oxide” and “a magnesium oxide hydrate”, and any otherdiversion of these phrases, are used herein interchangeably with respectto MgO.(H₂O)n.

MgO.(H₂O)n encompasses a form of magnesium oxide which is in a complexwith water molecule or molecules, at the indicated stoichiometric ratio(MgO:H₂O=1:n).

Without being bound by any particular theory as to the specific natureof this complexation, one or more water molecules are assumed to beadsorbed to the surface of one or more magnesium oxide molecules viaelectrostatic forces.

Thus, for example, when n equals 1, MgO.(H₂O)n is a monohydrate form ofmagnesium oxide, meaning that one molecule of MgO is complexed to onemolecule of water, and, when taken as a crystal, means that eachmolecule of MgO in the crystal interacts with one water molecule.

When n equals 2, MgO.(H₂O)n is a dihydrate form of magnesium oxide,meaning that one molecule of MgO is complexed to two molecules of water,and, when taken as a crystal, means that each molecule of MgO in thecrystal interacts with two water molecules.

When n equals, for example, 1.5, MgO.(H₂O)n is a hydrate form ofmagnesium oxide, in which 2 molecules of MgO are complexed to 3molecules of water, and, when taken as a crystal, means that the MgO andwater molecules in the crystal structure are arranged in a structurecomposed of clusters of 2 MgO molecules and 3 water molecules.

When n is lower than one, MgO.(H₂O)n is a hydrate form of magnesiumoxide in which several MgO molecules are complexed to one watermolecule, and, when taken as a crystal, means that means that the MgOand water molecules in the crystal structure are arranged in a structurecomposed of clusters of several MgO molecules and a respective lowernumber of water molecules.

As non-limiting examples, when n is 0.66, it means that 2 watermolecules are complexed to 3 MgO molecules and when n is 0.33, it meansthat one water molecule is complexed to 3 MgO molecules.

In some embodiments, n ranges from 0.3 to 1, and can be, for example,0.3, 0.33, 0.4, 0.5, 0.66, 0.75, 0.8 or 1. However, n values of 1.2,1.33, 1.5, 1.66, 1.75, 1.8, 2 are also contemplated.

Herein throughout, MgO is also referred to herein interchangeably asmagnesium oxide or periclase, and refers to a non-hydrated form ofmagnesium oxide, unless otherwise indicated.

Herein throughout, Mg(OH)₂ is also referred to herein interchangeably asmagnesium hydroxide, magnesium dihydroxide and brucite.

The composition disclosed herein comprises at least 1 weight percent (wt%) of MgO.(H₂O)n.

In some embodiments, the composition comprises MgO.(H₂O)n at aconcentration in the range of at least 10 wt % to at least 95 wt % of atotal weight of the composition.

In some embodiments, the composition consists of MgO.(H₂O)n, such thatits concentration is 100 wt % and the concentration of MgO and Mg(OH)₂is 0.

In some embodiments, the composition comprises a mixture of MgO.(H₂O)n,at any of the concentrations described herein, and one or both of MgOand Mg(OH)₂.

In some embodiments, the composition comprises from 10 to 90 wt % one orboth of MgO and Mg(OH)₂, and the balance is MgO.(H₂O)n.

In some embodiments, the composition comprises from 20-80 wt % one orboth of MgO and Mg(OH)₂, and the balance is MgO.(H₂O)n.

In some embodiments, the composition comprises from 30-70 wt % one orboth of MgO and Mg(OH)₂, and the balance is MgO.(H₂O)n.

In some embodiments, the composition comprises from 40-60 wt % one orboth of MgO and Mg(OH)₂, and the balance is MgO.(H₂O)n.

In some embodiments, the composition comprises 50 wt % of one or both ofMgO and Mg(OH)₂, and 50 wt % MgO.(H₂O)n.

In some embodiments, the composition is in a powder form, whichcomprises a plurality of particles.

In some embodiments, the particles have an average size that is fromabout 0.5 mm to about 1.5 mm.

In some embodiments, at least 50%, or at least 60%, or at least 70%, ofthe particles have a size of from about 0.2 mm to about 0.6 mm (30-60mesh).

In some embodiments, the composition is characterized by a surface areaof from about 30 m²/gram to about 40 m²/gram, or from about 32 m²/gramto about 38 m²/gram, or from about 34 m²/gram to about 36 m²/gram, orcan be equal to about 35 m²/gram. In some embodiments, the surface areais determined by BET measurements.

In some embodiments, the composition is a free-flowing powder,characterized by a bulk density lower than 1 gram/ml (e.g., of 0.90gram/ml).

In particular embodiments of the invention, the composition further maycomprise at least one additional ingredient selected from the groupconsisting of (a) water soluble vitamins, and (b) fat soluble vitamins.

According to an aspect of some embodiments, the composition comprises atherapeutic amount of Vitamin B₆.

In other embodiments of the present invention, the composition comprisestherapeutic amounts of Vitamin E and Vitamin D.

Various processes known to those skilled in the art can be used toprepare the composition as described herein. Exemplary processes aredescribed in Example 1 in the Examples section that follows.

The composition as described herein is characterized by improvedpharmacological features and, thus, can be advantageously formulatedinto a pharmaceutical composition.

According to an aspect of some embodiments of the present invention,there is provided a pharmaceutical composition which comprises thecomposition as described herein.

As used herein, a “pharmaceutical composition” or “medicament” refers toa preparation of one or more of the compounds or compositions comprisingtwo or more compounds as described herein, with other chemicalcomponents, such as pharmaceutically acceptable and suitable carriersand excipients.

The purpose of a pharmaceutical composition is to facilitateadministration of a compound or a composition comprising two or morecompounds, as described herein, to a subject.

The term “active ingredient” refers to a compound, or a compositioncomprising two or more compounds, as described herein, which isaccountable for a biological effect.

The terms “physiologically acceptable carrier” and “pharmaceuticallyacceptable carrier” which may be interchangeably used refer to a carrieror a diluent that does not cause significant irritation to an organismand does not abrogate the biological activity and properties of theadministered composition.

Herein the term “excipient” refers to an inert substance added to apharmaceutical composition to further facilitate administration of anactive ingredient. Examples, without limitation, of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils and polyethyleneglycols.

Techniques for formulation and administration of active ingredients arewell known in the art. Pharmaceutical compositions for use in accordancewith the present invention thus may be formulated in a conventionalmanner, optionally, but not necessarily, using one or morepharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the compounds orcompositions into preparations which can be used pharmaceutically.Proper formulation is dependent upon the route of administration chosen.The dosage may vary depending upon the dosage form employed and theroute of administration utilized. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition (see e.g., Fingl and Woodbury, 1975).

In some embodiments, the pharmaceutical composition is formulated fororal administration.

Compositions for oral administration include powders or granules,capsules or tablets, suspensions or solutions in water or non-aqueousmedia, sachets, pills, caplets. Thickeners, diluents, flavorings,dispersing aids, emulsifiers or binders may be desirable.

The amount of a composition to be administered will, of course, bedependent on the subject being treated, the severity of the affliction,the manner of administration, the judgment of the prescribing physician,etc.

The pharmaceutical composition may further comprise additionalpharmaceutically active or inactive agents. Such agents can be, forexample, vitamins, hormones, preservatives, growth factors,anti-microbial agents, anti-inflammatory agents.

In some embodiments, the pharmaceutical composition is formulated as aunit dosage form for oral administration.

As used herein and in the art, the phrase “dosage form” describes afinal physical form an active ingredient for consumption by a subject.The phrase “unit dosage form” describes physically discrete units, eachunit containing a predetermined quantity of the active ingredient,herein the disclosed composition, calculated to produce the desiredtherapeutic effect, optionally in association with at least onepharmaceutically acceptable carrier, diluent, excipient, additionalactive or non-active agents or combination thereof, as described herein.

In some embodiments, the pharmaceutical composition disclosed herein isformulated, for example, as sachets, pills, caplets, capsules, tablets,chewing gums and any other chewable composition, dragee-cores ordiscrete (e.g., separately packaged) units of powder, granules, orsuspensions or solutions in water or non-aqueous media

Pharmacological preparations for oral use can be made by grinding thecomposition as disclosed herein, optionally while using a solidexcipient, and processing the composition or mixture of granules, afteradding suitable auxiliaries if desired, to obtain tablets or drageecores.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, silicon dioxide, titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identification or tocharacterize different combinations of active doses.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of HPMC or gelatin as well as soft, sealed capsules madeof HPMC or gelatin and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules may contain the active ingredients in admixture withfiller such as lactose, or silicon dioxide, binders such as starches,lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active ingredient may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Optionally, formulations for oral administration further include aprotective coating, aimed at protecting or slowing enzymatic degradationof the preparation in the GI tract.

Composition unit dosage forms according to the present embodiments may,if desired, be presented in a pack or dispenser device, such as an FDA(the U.S. Food and Drug Administration) approved kit, which may containone or more unit dosage forms containing the composition as disclosedherein. The pack or dispenser device may, for example, comprise metal orplastic foil, such as, but not limited to a blister pack. The pack ordispenser device may be accompanied by instructions for administration.The pack may also be accompanied by a notice associated with thecontainer in a form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the compositions for humanadministration. Such notice, for example, may be of labeling approved bythe U.S. Food and Drug Administration for prescription drugs or of anapproved product insert.

Unit dosage forms comprising the composition as disclosed herein can beprepared, placed in an appropriate container, and labeled for use asmagnesium supplement, as described in further detail herein below.

According to some embodiments, the unit dosage form is identified (e.g.,in the abovementioned instructions for administration) for use once ortwice per day, optionally once per day.

According to some embodiments, the unit dosage form is identified (e.g.,in the abovementioned instructions for administration) for use such thata daily dose consists of one or two units of the unit dosage form, andoptionally one unit of the unit dosage form.

According to some embodiments, the unit dosage form is identified (e.g.,in the abovementioned instructions for administration) for use beforebed time.

In some embodiments, the unit dosage form comprises an amount of thecomposition as described herein which is equivalent to an amount ofelemental magnesium of from about 50 mg to about 2000 mg, or from about50 mg to about 1000 mg, or from about 50 mg to about 800 mg, or fromabout 100 mg to about 800 mg, or from about 300 to 800 mg or from about400 to 600 mg, or is about 520 mg. Any intermediate value within theindicated ranges is contemplated.

Herein, the term “equivalent to an amount of elemental magnesium” refersto the amount of material (by weight) which is contributed by themagnesium element alone, excluding any other element in the composition.

In a particular embodiment, the unit dosage form comprises Vitamin B₆ inan amount of from 2 to 30 mg, more preferably from 5 to 10 mg, and mostpreferably of 10 mg. A unit dosage form of the composition according topresent particular embodiments further comprises Vitamin D₃ in an amountof from 400 to 4000 IU, in other words from 10 to 100 μg, morepreferably from 400 to 1000 IU (10-25 μg).

In a further particular embodiment, the unit dosage form comprisesVitamin E in an amount of from 10 to 200 mg, more preferably from 20 to100 mg, and most preferably 50 mg.

Optionally, a unit dosage form is designed so as to facilitate divisionof a unit dosage form into two half-unit dosage forms. For example, apill, tablet or caplet may be scored so as to be readily broken in half.

In some embodiments, the pharmaceutical composition described herein, orthe unit dosage forms described herein, are packaged in packagingmaterial and identified for use as magnesium supplements, and/or in thetreatment of a subject in need of magnesium supplementation.

A pharmaceutical composition oral dosage form releases an activeingredient or agent in the stomach (from where the agent can be absorbedafter passing into the intestines) until the end of the gastricretention time, provided that the dosage form is capable of continuouslyreleasing an active agent over such a period of time.

However, it is to be appreciated that the time during which the activeagent is absorbed into the body may be longer than the gastric retentiontime, as absorption of the agent into the body may continue for asignificant time period when the dosage form (or the remaining portionof the dosage form) is in the intestines. The duration of the timeperiod during which absorption occurs after the dosage form has exitedthe stomach will depend on various factors, such as the length of the“absorption window” and the speed at which intestinal contents passthrough the intestines.

When a pharmaceutical composition according to the present embodimentsis orally administered, it releases free magnesium ions in the stomach.

By “free magnesium ions” it is meant Mg²⁺ ions which are not complexedor otherwise bound to another moiety (as in the case of, for example,magnesium citrate or MgO).

It is assumed that under conditions of a human stomach, the freemagnesium ions are generated by conversion of the administered magnesiumsalt into a magnesium chloride salt, which is completely dissolved inthe aqueous environment and thus generates the free magnesium ions.

In some embodiments, the pharmaceutical composition unit dosage form asdescribed herein is characterized as capable of generating freemagnesium ions under physiological conditions of a human stomach, in anamount which is at least 50%, at least 60%, at least 70%, at least 80%,or at least 90%, and even 100% of its magnesium content.

In some embodiments, generation of magnesium ions in the stomach iseffected during a time period that is equivalent to a retention time ofthe pharmaceutical composition in a human stomach.

In some embodiments, such a time period ranges from 30 minutes (0.5hour) to 6 hours.

The capability of an exemplary pharmaceutical composition according tosome embodiments of the present invention to dissolve in an acidicaqueous solution and thereby generate free magnesium ions has beendemonstrated (see Example 2 in the Examples section the follows).

In some embodiments, a pharmaceutical composition unit dosage form asdescribed herein is characterized as generating free magnesium ions inan amount which is least 50%, at least 60%, at least 70%, or at least80%, of its magnesium content, when dissolved in an acidic aqueoussolution for 45 minutes at room temperature.

In some embodiments, the acidic aqueous solution is a 0.1N HCl solutionthat is equivalent to the acidity of a stomach.

Some embodiments of the present invention are, therefore, based on thefindings that compositions that comprise magnesium oxide and/or ahydrate form of magnesium oxide as described herein and/or magnesiumhydroxide, including pharmaceutical compositions containing orconsisting of such compositions, are characterized by a high dissolutionrate and level in an aqueous solution, in which free magnesium ions arereleased. Without being bound by any particular theory, it is suggestedthat the high dissolution rate and level of such compositions attributesto the high level of magnesium cellular uptake, which can be representedas the value [Mg²⁺]i, which results from orally administering magnesiumoxide-type salt-containing compositions as described herein.

According to an aspect of some embodiments of the present invention,there is provided a pharmaceutical composition unit dosage form for oraladministration, which comprises a magnesium oxide-type salt, includingMgO and/or Mg(OH)₂ and/or MgO.(H₂O)n, wherein n is any value from 0.1 to2, as described herein.

In some embodiments, such a composition is characterized as capable ofgenerating free magnesium ions from at least 50% of its magnesiumcontent under physiological conditions of a human stomach, as describedherein.

In some embodiments, such a composition is characterized as capable ofgenerating free magnesium ions from at least 50% of its magnesiumcontent when dissolved in an acidic aqueous solution, as describedherein, for 45 minutes at room temperature.

In some of these embodiments, the magnesium oxide-type salt comprisesMgO. In some embodiments, it comprises a mixture of MgO and MgO.(H₂O)n,as described herein. In some embodiments, it comprises a mixture of MgOand Mg(OH)₂. In some embodiments, it comprises a mixture of MgO, Mg(OH)₂and MgO.(H₂O)n. In some embodiments, it comprises solely MgO.(H₂O)n.

Preferably, the composition has a BET surface area ranging from 30m²/gram to 40 m²/gram.

In some of these embodiments, one or more of the pharmaceuticalcomposition unit dosage form(s) are packaged in a packaging material andidentified for use as a magnesium supplement and/or in the treatment ofa subject in need of magnesium supplementation.

Further according to embodiments of the present invention, there isprovided a use of a composition as described herein in the manufactureof a magnesium supplement, which can optionally be used as a medicamentfor treating a subject in need of magnesium supplementation.

Further according to embodiments of the present invention, there isprovided a composition or a pharmaceutical composition as describedherein, which is identified for use as a magnesium supplement, and/or isidentified for use in the treatment of a subject in need of magnesiumsupplementation.

Further according to some embodiments of the present invention, there isprovided a magnesium supplement which comprises any of the compositionsand pharmaceutical compositions as described herein.

Further according to some embodiments of the present invention, there isprovided a method of treating a subject in need of magnesiumsupplementation, which is effected by administering to the subject atherapeutically effective amount of any of the compositions of thepharmaceutical compositions described herein.

In some embodiments, the method is effected by orally administering thecomposition or pharmaceutical composition.

In some embodiments, the therapeutically effective amount is such thatis equivalent to from 50 to 2000 mg of elemental magnesium per day.

The therapeutically effective amount and regimen depend on the age,weight and health condition of the subject.

For example, generally healthy subjects typically require atherapeutically effective amount of elemental magnesium that ranges from5 mg/kg body/day to 10 mg/kg body/day. Such an amount is accountable formaintaining a desired magnesium level and/or to prevent magnesiumdeficiency or hypomagnesaemia.

This amount can be elevated in generally healthy subjects thatexperience extensive physical efforts, for example, by exercising sport.

This amount can be elevated in generally healthy subjects that are undermedication, as detailed herein.

This amount can further be elevated in generally healthy subjects whowere diagnosed as suffering from magnesium deficiency, as detailedherein.

This amount can be elevated in subjects who suffer from a conditionwhich is caused by magnesium deficiency, which causes magnesiumdeficiency and/or which is treatable by an elevated level of magnesium,as detailed herein.

In some embodiments, administering is effected once daily, however, canbe effected from once up to 4 times a day.

By “magnesium deficiency”, reference is made to serum magnesium level,cellular magnesium level and/or bone magnesium level.

In any of the aspects described herein, magnesium supplementation refersto maintaining a desired magnesium level and/or to prevent magnesiumdeficiency or hypomagnesaemia.

In any of the aspects described herein, treating a subject in need ofmagnesium supplementation refers to treating subjects who experienceextensive physical efforts, as described herein, who take medicationsthat typically cause magnesium deficiency, who are diagnosed assuffering from magnesium deficiency, and/or suffer from a conditionwhich is caused by magnesium deficiency, which causes magnesiumdeficiency and/or which is treatable by an elevated level of magnesium,as detailed herein.

Exemplary subjects who can benefit from magnesium supplementation arethose suffering from any one or more of hypomagnesaemia, coronary arterydisease (CAD), chronic heart failure, diabetes mellitus, metabolicsyndrome, an abnormal muscle excitability, a convulsive disorder, apsychiatric disturbance, a calcium and/or potassium abnormality, achronic intoxication, alcoholism, drug abuse, renal wasting, stress,neurosis, a nervous disorder, an endocrine-metabolic disorder,malnutrition, constipation, preeclampsia, leg cramps, cerebral palsy,depression, asthma, a cardiovascular disease, an ischemic heart disease,cardiac arrhythmias, hypertension, pregnancy-induced hypertension,stroke, a cerebrovascular disease, osteoporosis, alcohol withdrawal,preterm labor, fatigue, renal stones, kidney stones, headache, migraine,altitude sickness, premenstrual syndrome, fibromyalgia, muscle weakness,insulin resistance, bronchospasms, hyperlipidemia, mitral valveprolapse, and neonatal encephalopathy.

Exemplary subjects who may benefit from magnesium supplementation arehuman beings of any age or condition, including fetuses, babies,adolescents, adults, elderly subjects, nursing and/or pregnant mothers,and healthy and/or sick patients.

It is expected that, during the life of a patent maturing from thisapplication, many relevant additional conditions which are associatedwith magnesium deficiency or which are treatable by magnesiumsupplementation will be identified and the scope of conditions isintended to include any and all of newly identified conditions a priori.

As used herein the term “about” refers to ±10%.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor structure may include additional ingredients, steps and/or parts, butonly if the additional ingredients, steps and/or parts do not materiallyalter the basic and novel characteristics of the claimed composition,method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention maybe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible subranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicate number and asecond indicate number and “ranging/ranges from” a first indicate number“to” a second indicate number are used herein interchangeably and aremeant to include the first and second indicated numbers and all thefractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a condition,substantially ameliorating clinical or aesthetical symptoms of acondition or substantially preventing the appearance of clinical oraesthetical symptoms of a condition.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as definedhereinabove and as claimed in the claims section below find experimentalsupport in the following non-limiting examples.

EXAMPLES

Reference is now made to the following examples, which, together withthe above descriptions, illustrate some embodiments of the invention ina non-limiting fashion.

Example 1 MgO.(H₂O)n-Containing Formulation

Characterization:

A homogenous and stable granular powder containing MgO.(H₂O)n asco-product of high pure MgO, extracted from the Dead Sea, and Mg(OH)₂obtained from ICL Industrial Products (Beer-Sheva Israel), with typicalmelting point, particle size, and analytical specifications, is utilizedfor formulating a magnesium-containing product as described herein.

One such exemplary magnesium-containing powder exhibits the followingcharacteristics:

Purity of about 96.4%;

Loss on ignition of about 31.0%;

Bulk density of about 0.90 gram/mL;

Residual amount of non-Mg impurities of about 0.7%;

BET surface area of about 35 m²/gram; and

A particle size distribution, as determined by Laser Diffraction Method,and is expressed according to ASTM E 11-70 (1995) standard, as follows:

ASTM +30 mesh (0.595 mm)−8.0-20.0%

ASTM −30+60 mesh (0.595-0.250 mm)−60.0-70.0%

ASTM −60+100 mesh (0.250-0.149 mm)−5.0-25.0%

ASTM −100 mesh (0.149 mm)−1.0-8.0%

As shown herein, the particles vary in size but exhibit a d₇₀ (averageparticle size of 70% of the granules) of 30-60 mesh.

FIG. 4 presents a representative photograph of a granularmagnesium-containing particle, showing it has a white gray color.

Formulation:

An oral unit-dosage form containing magnesium oxide hydrate of thepresent invention is prepared by compacting a powder as describedherein, optionally mixed with additional active and non-activeingredients, into tablets.

In an exemplary procedure, tablets were prepared by direct compaction(batch size of 200 kg) using an 8-station Riva Piccola tablet machineformatted with 11 mm round, standard concave punches, to a target tabletweight of 1000 mg±3%.

Thus, a granular composition containing Mg.(H₂O)n, optionally mixed withMg(OH)₂ and/or MgO (900 mg), Microcrystalline cellulose (200 mg),Copovidone (50 mg) and Crospovidone (0.0-20 mg) was blended in alow-shear mixer for five minutes. Colloidal silicon dioxide (5 mg) andoptionally Magnesium stearate (5 mg) were then added and the resultingmixture was blended for an additional two minutes. The final blend waspassed through a 0.8 mm sieve and the obtained powder was compacted intotablets using the Piccola press, as described herein, at an appliedforce of 20-22 kN.

Coated tablets are prepared by applying an enteric coating, usingacceptable polymers like Eudragit L-30 D-55, hydroxy propylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate andAcryl-EZE®, to achieve 5% weight gain of the coating.

In an exemplary process, tablets were film-coated using an O'HaraLabCoat IIX side-vented coating machine fitted with a 15″ coating panand a Schlick ABC two-fluid spray nozzle. The general process conditionsused were as follows:

Tablet charge (kg) 2.0;

Solids content in coating suspension 12.5% w/w;

Target weight gain 3% w/w;

Inlet air temperature 60° C.;

Pan speed 15 rpm;

Inlet air volume 255 m³·h⁻¹;

Atomizing air pressure 1.3 bar;

Pattern air pressure 2.3 bar;

Spray rate 15 g·min⁻¹.

Alternatively, a granular composition, containing Mg.(H₂O)n, optionallymixed with Mg(OH)₂ and/or MgO (900 mg), is formulated into HPMC orGelatin Capsules (e.g., No. 00), using silicon dioxide as an excipient,in an amount of up to 5 mg per 1 gram composition (per 1 capsule).Optionally, a composition is formulated to contain at least 50 mg ofVitamin E, at least 10 mg of Vitamin B₆ and preferably 400IU of VitaminD₃.

Example 2

Dissolution Tests

The solubility of magnesium-containing capsules was tested in an assayperformed according to USP specifications. In this assay, the solubilityof a variety of magnesium-containing samples was tested as a function ofthe magnesium salt/complex used and the type of the formulation.

A round-bottomed flask containing 100 ml 0.1 N hydrochloric acid (HCl),which is the equivalent to stomach acidity, was heated to 37° C. Atested magnesium-containing sample was then placed inside the flask andstirred at 75 rpm by a mechanical agitator. After 45 minutes, thequantity of dissolved magnesium was measured by titration with sodiumhydroxide (0.2 mol·dm⁻³).

The results are presented in Table 1 below and show that the capsulescontaining magnesium oxide and/or a hydrate thereof exhibited thehighest solubility of all types tested, both percentagewise, as thepercent of magnesium (relative to the amount of the elemental magnesiumin the capsule) and on an absolute scale (of the quantity of dissolvedmagnesium).

TABLE 1 Percent of Quantity of Magnesium Amount of Magnesium dissolvedElemental which as Magnesium dissolved measured per unit Magnesium Typeof Company (mg) by Assay (mg) Source encapsulation Name 323 87% 370Powdered Capsule, Naveh MgO and/or 625 mg Pharma a hydrate form thereof158 63% 250 Magnesium Capsule Solgar Citrate XXX 44 45% 98.6 MagnesiumChewable Diasporal Citrate Tablet

Optical images of the tested solutions are shown in FIGS. 5A-5C. FIG. 5Ashows the experimental setup; a magnesium sample can be seen in thecenter flask. The clear solution is indicative of complete dissolution.FIG. 5B shows a close-up of the Solgar capsules, containing magnesiumcitrate. FIG. 5C shows a close-up of Diasporal chewable tablets,containing magnesium citrate.

The examples set forth above are given to provide those of skill in theart with disclosure and description of how to make and use variousembodiments of the methods disclosed herein, and is not intended tolimit the scope of the invention.

A composition and/or method described herein may be useful for purposesdescribed herein, such as maintaining and/or improving in humans thehealth conditions related to magnesium deficiency.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be interpreted as necessarilylimiting.

The scope of the invention is to be interpreted in accordance with thesubstance defined in the following claims.

REFERENCES

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What is claimed is:
 1. A method of treating leg cramps in a subject inneed thereof and/or supplementing magnesium in a subject undergoingextensive exercise, the method comprising orally administering to thesubject a therapeutically effective amount of a composition comprising ahydrate form of magnesium oxide, denoted as MgO.(H₂O)n, at aconcentration in a range of from 1 to 100 weight percent (wt %), where nis any value from 0.1 to 2, wherein an amount of elemental magnesium insaid therapeutically effective amount is in a range of from 100 mg to520 mg.
 2. The method of claim 1, wherein orally administering thecomposition is effected daily.
 3. The method of claim 2, wherein orallyadministering the composition is effected before bed time.
 4. The methodof claim 1, wherein an amount of elemental magnesium in saidtherapeutically effective amount is in a range of from 200 mg to 520 mg.5. The method of claim 1, wherein an amount of elemental magnesium insaid therapeutically effective amount is in a range of from 360 mg to440 mg.
 6. The method of claim 1, wherein said composition comprises:Magnesium oxide hydrate MgO.(H₂O)n, at a concentration in a range offrom 1 to 100 wt %, wherein n in any value from 0.1 to 2, and MgO at aconcentration in a range of from 0 to 99 wt %; or Magnesium oxidehydrate MgO.(H₂O)n, at a concentration in a range of from 1 to 100 wt %,wherein n in any value from 0.1 to 2, and Mg(OH)₂, at a concentration ina range of from 0 to 99 wt %; or Magnesium oxide hydrate MgO.(H₂O)n, ata concentration in a range of from 1 to 100 wt %, wherein n is any valuefrom 0.1 to 2, Mg(OH)₂ at a concentration in a range of from 0 to 99 wt%, and MgO at a concentration in a range of from 0 to 99 wt %.
 7. Themethod of claim 1, wherein n is in a range of from 0.3 to
 1. 8. Themethod of claim 1, wherein a concentration of said MgO.(H₂O)n in saidcomposition is selected from the group including: at least 10 wt %, atleast 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, atleast 60 wt %, at least 70 wt % or at least 80 wt % of a total weight ofthe composition.
 9. The method of claim 1, wherein said composition isin a form of a plurality of particles.
 10. The method of claim 1,wherein said composition further comprises an excipient selected fromthe group consisting of starch and cellulose derivatives.
 11. The methodof claim 1, wherein said composition further comprises at least oneadditional agent selected from the group consisting of Vitamin D,Vitamin B₆, and Vitamin E.
 12. The method of claim 1, wherein saidcomposition is formulated as a unit dosage form for oral administration,wherein an amount of elemental magnesium in said unit dosage form is ina range of from 100 mg to 520 mg.
 13. The method of claim 12, wherein anamount of elemental magnesium in said unit dosage form is in a range offrom 200 mg to 520 mg.
 14. The method of claim 12, wherein an amount ofelemental magnesium in said unit dosage form is in a range of from 360mg to 440 mg.
 15. The method of claim 12, wherein said unit dosage formis a capsule.
 16. The method of claim 12, wherein said unit dosage formis identified for use such that a daily dose consists of one unit ofsaid unit dosage form.
 17. The method of claim 12, wherein said unitdosage form is identified for use before bed time.
 18. The method ofclaim 1, being for treating leg cramps in said subject in need thereof.19. The method of claim 1, being for supplementing magnesium in saidsubject undergoing extensive exercise.
 20. The method of claim 1,wherein said extensive exercise is sport exercise.